The present invention relates to compounds that can be used in the medicinal field to treat, prophylactically or otherwise, uncontrolled or abnormal proliferation of human tissues. Specifically, the present invention relates to compounds that inhibit the farnesyl transferase enzyme, which has been determined to activate ras proteins that in turn activate cellular division and are implicated in cancer, restenosis, atherosclerosis, and psoriasis.
Ras protein (or p21) has been examined extensively because mutant forms are found in 20% of most types of human cancer and greater than 50% of colon and pancreatic carcinomas (Gibbs J. B., Cell, 1991;65:1, Cartwright T., et al., Chimica. Oggi., 1992;10:26). These mutant ras proteins are deficient in the capability for feedback regulation that is present in native ras, and this deficiency is associated with their oncogenic action since the ability to stimulate normal cell division cannot be controlled by the normal endogenous regulatory cofactors. The recent discovery that the transforming activity of mutant ras is critically dependent on posttranslational modifications (Gibbs J., et al., Microbiol. Rev., 1989;53:171) has unveiled an important aspect of ras function and identified novel prospects for cancer therapy.
In addition to cancer, there are other conditions of uncontrolled cellular proliferation that may be related to excessive expression and/or function of native ras proteins. Postsurgical vascular restenosis is such a condition. The use of various surgical revascularization techniques such as saphenous vein bypass grafting, endarterectomy, and transluminal coronary angioplasty are often accompanied by complications due to uncontrolled growth of neointimal tissue, known as restenosis. The biochemical causes of restenosis are poorly understood and numerous growth factors and protooncogenes have been implicated (Naftilan A. J., et al., Hypertension, 1989;13:706 and J. Clin. Invest., 83:1419; Gibbons G. H., et al., Hypertension, 1989;14:358; Satoh T., et al., Molec. Cell. Biol., 1993;13:3706). The fact that ras proteins are known to be involved in cell division processes makes them a candidate for intervention in many situations where cells are dividing uncontrollably. In direct analogy to the inhibition of mutant ras related cancer, blockade of ras dependent processes has the potential to reduce or eliminate the inappropriate tissue proliferation associated with restenosis, particularly in those instances where normal ras expression and/or function is exaggerated by growth stimulatory factors.
Ras functioning is dependent upon the modification of the proteins in order to associate with the inner face of plasma membranes. Unlike other membrane-associated proteins, ras proteins lack conventional transmembrane or hydrophobic sequences and are initially synthesized in a cytosol soluble form. Ras protein membrane association is triggered by a series of posttranslational processing steps that are signaled by a carboxyl terminal amino acid consensus sequence that is recognized by protein farnesyl transferase (PFT). This consensus sequence consists of a cysteine residue located four amino acids from the carboxyl terminus, followed by two lipophilic amino acids and the C-terminal residue. The sulfhydryl group of the cysteine residue is alkylated by farnesylpyrophosphate in a reaction that is catalyzed by protein farnesyl transferase. Following prenylation, the C-terminal three amino acids are cleaved by an endoprotease and the newly exposed alpha-carboxyl group of the prenylated cysteine is methylated by a methyl transferase. The enzymatic processing of ras proteins that begins with farnesylation enables the protein to associate with the cell membrane. Mutational analysis of oncogenic ras proteins indicates that these posttranslational modifications are essential for transforming activity. Replacement of the consensus sequence cysteine residue with other amino acids gives a ras protein that is no longer farnesylated, fails to migrate to the cell membrane and lacks the ability to stimulate cell proliferation (Hancock J. F., et al., Cell, 1989;57:1617, Schafer W. R., et al., Science, 1989;245:379, Casey P. J., Proc. Natl. Acad. Sci. USA, 1989;86:8323).
Recently, protein farnesyl transferases (PFTs), also referred to as farnesyl proteintransferases (FPTs) have been identified, and a specific PFT from rat brain was purified to homogeneity (Reiss Y., et al., Biochem. Soc. Trans., 1992;20:487-88). The enzyme was characterized as a heterodimer composed of one alpha-subunit (49 kDa) and one beta-subunit (46 kDa), both of which are required for catalytic activity. High level expression of mammalian PFT in a baculovirus system and purification of the recombinant enzyme in active form has also been accomplished (Chen, W. J., et al., J. Biol. Chem., 1993;268:9675).
In light of the foregoing, the discovery that the function of oncogenic ras proteins is critically dependent on their posttranslational processing provides a means of cancer chemotherapy through inhibition of the processing enzymes. The identification and isolation of a protein farnesyl transferase that catalyzes the addition of a farnesyl group to ras proteins provides a promising target for such intervention. Ras farnesyl transferase inhibitors have been shown to have anticancer activity in several recent articles.
Ras inhibitor agents act by inhibiting farnesyl transferase, the enzyme that anchors the protein product of the ras gene to the cell membrane. The role of the ras mutation in transducing growth signals within cancer cells relies on the protein being in the cell membrane, so with farnesyl transferase inhibited, the ras protein will stay in the cytosol and be unable to transmit growth signals: these facts are well-known in the literature.
A peptidomimetic inhibitor of farnesyl transferase B956 and its methyl ester B1086 at 100 mg/kg have been shown to inhibit tumor growth by EJ-1 human bladder carcinoma, HT1080 human fibrosarcoma, and human colon carcinoma xenografts in nude mice (Nagasu, T., et al., Cancer Res., 1995;55:5310-5314). Furthermore, inhibition of tumor growth by B956 has been shown to correlate with inhibition of ras posttranslational processing in the tumor. Other ras farnesyl transferase inhibitors have been shown to specifically prevent ras processing and membrane localization and are effective in reversing the transformed phenotype of mutant ras containing cells (Sepp-Lorenzino L., et al., Cancer Res., 1995;55:5302-5309).
In another report (Sun J., et al., Cancer Res., 1995;55:4243-4247), a ras farnesyl transferase inhibitor FT1276 has been shown to selectively block tumor growth in nude mice of a human lung carcinoma with K-ras mutation and p53 deletion. In yet another report, daily administration of a ras farnesyl transferase inhibitor L744,832 caused tumor regression of mammary and salivary carcinomas in ras transgenic mice (Kohl et al., Nature Med., 1995; 1(8):792-748). Thus, ras farnesyl transferase inhibitors have benefit in certain forms of cancer, particularly those dependent on oncogenic ras for their growth. However, it is well-known that human cancer is often manifested when several mutations in important genes occur, one or more of which may be responsible for controlling growth and metastases. A single mutation may not be enough to sustain growth and only after two or three mutations occur, tumors can develop and grow. It is therefore difficult to determine which of these mutations may be primarily driving the growth in a particular type of cancer. Thus, ras farnesyl transferase inhibitors can have therapeutic utility in tumors not solely dependent on oncogenic forms of ras for their growth. For example, it has been shown that various ras FT-inhibitors have antiproliferative effects in vivo against tumor lines with either wild-type or mutant ras (Sepp-Lorenzino, supra). In addition, there are several ras-related proteins that are prenylated. Proteins such as R-Ras2/TC21 are ras-related proteins that are prenylated in vivo by both farnesyl transferase and geranylgeranyl transferase I (Carboni, et al., Oncogene, 1995;10:1905-1913). Therefore, ras farnesyl transferase inhibitors could also block the prenylation of the above proteins and therefore would then be useful in inhibiting the growth of tumors driven by other oncogenes.
With regard to restenosis and vascular proliferative diseases, it has been shown that inhibition of cellular ras prevents smooth muscle proliferation after vascular injury in vivo (Indolfi C., et al., Nature Med., 1995;1(6):541-545). This report definitively supports a role for farnesyl transferase inhibitors in this disease, showing inhibition of accumulation and proliferation of vascular smooth muscle.
Provided by the present invention are compounds having the Formula I 
wherein
Ra, Rb, and Rc are each independently C1-C6 alkyl or hydrogen;
Rd, Re, Rf, and Rg are each independently C1-C6 alkyl, hydrogen, or phenyl; 
R4 is aryl, substituted aryl, or C1-C6 alkyl; and
each n is independently 0 to 5, m is 2 to 4, and the pharmaceutically acceptable salts, and prodrugs thereof.
In a preferred embodiment of Formula I, Y is xe2x80x94Oxe2x80x94.
In another preferred embodiment of Formula I, 
In another preferred embodiment of Formula I, Ra is hydrogen, Rb is methyl, and Rc is hydrogen.
In another preferred embodiment of Formula I, R3 is 
In another preferred embodiment of Formula I, R3 is 
In another preferred embodiment of Formula I, R2 is xe2x80x94CH2CH2-phenyl or xe2x80x94CH2CH2-substituted phenyl.
In another preferred embodiment of Formula I, 
In another preferred embodiment of Formula I, 
In another preferred embodiment of Formula I, R3 is xe2x80x94(CH2)nxe2x80x94C1-C6 alkyl.
In another preferred embodiment of Formula I, R3 is 
In a more preferred embodiment, the present invention provides the following compounds:
[S-(R*,R*)]-[1-{[2-(4-Benzyloxy-phenyl)-1-phenethylcarbamoyl-ethyl]-methyl-carbamoyl}-2-(1H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester;
[S-(R*,R*)]-[1-{[2-(4-Benzyloxy-phenyl)-1-(2-methyl-2-phenyl-propylcarbamoyl)-ethyl]-methyl-carbamoyl}-2-1H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester;
[S-(R*,R*)]-[2-1H-Imidazol-4-yl)-1-(methyl-{1-(2-methyl-2-phenyl-propylcarbamoyl)-2-[4-(pyridin-2-ylmethoxy)-phenyl]-ethyl}-carbamoyl)-ethyl]-carbamic acid benzyl ester;
[S-(R*,R*)]-2-(3-Benzyl-3-methyl-ureido)-N-[2-(4-benzyloxy-phenyl)-1-(2-methyl-2-phenyl-propyl-carbamoyl)-ethyl]-3-(1H-imidazol-4-yl)-N-methyl-propionamide;
[S-(R*,R*)]-[1-{[2-(4-Benzyloxy-phenyl)-1-[(1-phenyl-cyclobutylmethyl)-carbamoyl]-ethyl}-methyl-carbamoyl)-2-(3H-imidazol-4-yl)-ethyl]-carbanic acid benzyl ester;
[S-(R*,R*)]-[2-(3H-Imidazol-4-yl)-1-{methyl-[1-(2-methyl-2-phenyl-propylcarbamoyl)-2-phenyl-ethyl]-carbarmoyl}ethyl-carbamic acid benzyl ester; and
[S-(R*,R*)]-[2-(3H-Imidazol-4-yl)-1-{methyl-[3-methyl-1-(2-methyl-2-phenyl-propylcarbamoyl)-butyl]-carbamoyl}-ethyl-carbamic acid benzyl ester.
In another more preferred embodiment, the present invention provides the following compounds:
[S-(R*,R*)]-[1-({2-(4-Benzyloxy-phenyl)-1-[2-(2-fluoro-phenyl)-ethyl-carbamoyl]-ethyl}-methyl-carbamoyl)-2-(3H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester;
[S-(R*,R*)]-[1-{[2-(4-Benzyloxy-phenyl)-1-(2-pyridin-2-yl-ethyl-carbamoyl]-ethyl]-methyl-carbamoyl}-2-(3 H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester;
[S-(R*,R*)]-[1-{[2-(4-Benzyloxy-phenyl)-1-(2,2-diphenyl-ethylcarbamoyl)-ethyl]-methyl-carbamoyl}-2-(3H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester;
[S-(R*,R*)]-[1-{[2-(4-Benzyloxy-phenyl)-1-(2-phenyl-propylcarbamoyl)-ethyl]-methyl-carbamoyl}-2-(3H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester;
[S-(R*,R*)]-(2-(3H-Imidazol-4-yl)-1-{methyl-[3-methyl-1-(2-methyl-2-phenyl-propylcarbamoyl)-butyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester;
[S-(R*,R*)]-[1-{[2-(4-Benzyloxy-phenyl)-1-(1-methyl-2-phenyl-ethylcarbamoyl)-ethyl]-methyl-carbamoyl}-2-(3H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester;
[S-(R*,R*)]-[1-({2-(4-Benzyloxy-phenyl)-1-[(1-phenyl-cyclopropyl-methyl)-carbamoyl]-ethyl}-methyl-carbamoyl)-2-(3H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester;
[S-(R*,R*)]-[1-{[2-(4-Chloro-phenyl)-1-(2-methyl-2-phenyl-propylcarbamoyl)-ethyl]-methyl-carbamoyl}-2-(3H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester;
[S-(R*,R*)]-2-(3-Benzyl-ureido)-3-(3H-imidazol-4-yl)-N-methyl-N-{1-(2-methyl-propyl-carbamoyl)-2-[4-(pyridin-4-ylmethoxy)-phenyl]-ethyl}-propionamide;
[S-(R*,R*)]-[1-{[2-(4-Benzyloxy-phenyl)-1-(1-methyl-2-phenyl-ethylcarbamoyl)-ethyl]-methyl-carbamoyl}-2-(3H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester;
[S-(R*,R*)]-(2-(3H-Imidazol-4-yl)-1-{methyl-[1-(2-methyl-2-phenyl-propylcarbamoyl)-2-p-tolyl-ethyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester;
[S-(R*,R*)]-(2-(3H-Imadozol-4-yl)-1-{[2-(4-methoxy-phenyl)-1-(2-methyl-2-phenyl-propylcarbamoyl)-ethyl]-methyl-carbamoyl}-ethyl)-carbamic acid benzyl ester;
[S-(R*,R*)]-2-(3-Benzyl-ureido)-3-(3H-imidazol-4-yl)-N-methyl-N-[1-(2-methyl-2-phenyl-propylcarbamoyl)-2-phenyl-ethyl]-propionamide; and
[S-(R*,R*)]-[1-[(2-(4-Benzyloxy-phenyl)-1-{[1-(2-fluoro-phenyl)-cyclopropylmethyl]-carbamoyl}ethyl)-methyl-carbamoyl]-2-(3H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester.
Also provided is a method of treating cancer, the method comprising administering to a patient having cancer a therapeutically effective amount of a compound of Formula I.
Also provided is a method of treating or preventing restenosis, the method comprising administering to a patient having restenosis or at risk of having restenosis a therapeutically effective amount of a compound of Formula I.
Also provided is a method of treating atherosclerosis, the method comprising administering to a patient having atherosclerosis a therapeutically effective amount of a compound of Formula I.
Also provided is a method of treating psoriasis, the method comprising administering to a patient having psoriasis a therapeutically effective amount of a compound of Formula I.
Also provided is a pharmaceutical composition that comprises a compound of Formula I.
The present invention provides compounds having the Formula I. 
wherein
Ra Rb, and Rc are each independently C1-C6 alkyl or hydrogen;
Rd, Re, Rf, and Rg are each independently C1-C6 alkyl, hydrogen, or phenyl; 
R4 is aryl, substituted aryl, or C1-C6 alkyl; and each n is independently 0 to 5, m is 2 to 4, and the pharmaceutically acceptable salts, and prodrugs thereof.
The term xe2x80x9calkylxe2x80x9d means a straight or branched hydrocarbon having from 1 to 6 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like.
The alkyl groups of the present invention include substituted alkyl groups. Examples of suitable substituents include, but are not limited to, halogen, xe2x80x94OC1-C6 alkyl, xe2x80x94SC1-C6 alkyl, CF3, xe2x80x94NO2, xe2x80x94CN, phenyl, xe2x80x94OH, xe2x80x94SH, xe2x80x94NH2, xe2x80x94NHC1-C6 alkyl, or xe2x80x94N(C1-C6 alkyl)2.
The term xe2x80x9carylxe2x80x9d means an aromatic ring which is a phenyl, 5-fluorenyl, 1-naphthyl, or 2-naphthyl group, unsubstituted or substituted by 1 to 3 substituents selected from alkyl, phenyl, O-phenyl, O-alkyl and S-alkyl, OH, SH, F, Cl, Br, I, CF3, NO2, NH2, NHCH3, N(CH3)2, NHCO-alkyl, (CH2)mCO2H, NHC1-C6 alkyl, N(C1-C6 alkyl)2, (CH2)mCO2-alkyl, (CH2)mSO3H, (CH2)mPO3H2, (CH2)mPO3(alkyl)2, (CH2)mSO2NH2, and (CH2)mSO2NH-alkyl wherein alkyl is defined as above and m=0, 1, 2, or 3.
The term xe2x80x9cheteroarylxe2x80x9d means a heteroaromatic ring which is a 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 3-, or 4-pyridyl, imidazolyl, 2-, 3-, 4-, 5-, 6-, or 7-indoxyl group, unsubstituted or substituted by 1 or 2 substituents from the group of substituents described above for aryl.
The symbol xe2x80x9cxe2x80x94xe2x80x9d means a bond.
The term xe2x80x9cpatientxe2x80x9d means all animals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, and pigs.
A xe2x80x9ctherapeutically effective amountxe2x80x9d is an amount of a compound of the present invention that when administered to a patient ameliorates a symptom of restenosis, cancer, atherosclerosis, or psoriasis, or prevents restenosis. A therapeutically effective amount of a compound of the present invention can be easily determined by one skilled in the art by administering a quantity of a compound to a patient and observing the result. In addition, those skilled in the art are familiar with identifying patients having cancer, restenosis, atherosclerosis, or psoriasis, or who are at risk of having restenosis.
The term xe2x80x9ccancerxe2x80x9d includes, but is not limited to, the following cancers:
breast;
ovary;
cervix;
prostate;
testis;
esophagus;
glioblastoma;
neuroblastoma;
stomach;
skin, keratoacanthoma;
lung, epidermoid carcinoma, large cell carcinoma, adenocarcinoma;
bone;
colon, adenocarcinoma, adenoma;
pancreas, adenocarcinoma;
thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma;
seminoma;
melanoma;
sarcoma;
bladder carcinoma;
uterine;
liver carcinoma and biliary passages;
kidney carcinoma;
myeloid disorders;
lymphoid disorders, Hodgkins, hairy cells; buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx;
small intestine;
colon-rectum, large intestine, rectum;
brain and central nervous system; and
leukemia.
The term xe2x80x9cpharmaceutically acceptable salts, and prodrugsxe2x80x9d as used herein refers to those carboxylate salts, amino acid addition salts, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term xe2x80x9csaltsxe2x80x9d refers to the relatively nontoxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free-base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laureate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphtholate mesylate, glucoheptonate, lactobionate and laurylsulphonate salts, and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. (See, for example, Berge, S. M. et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. Pharm. Sci., 1977;66:1-19 which is incorporated herein by reference.)
The term xe2x80x9cprodrugxe2x80x9d refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. A thorough discussion is provided in Higuchi, T. and Stella, V., xe2x80x9cPro-drugs as Novel Delivery Systems,xe2x80x9d Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward, B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference.
The compounds of the present invention can be administered to a patient alone or as part of a composition that contains other components such as excipients, diluents, and carriers, all of which are well-known in the art. The compositions can be administered to humans and animals either orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments, or drops), or as a buccal or nasal spray.
Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), Cremophor EL (a derivative of castor oil and ethylene oxide; purchased from Sigma Chemical Co., St. Louis, Mo.) and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, as for example, glycerol; (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin; (f) absorption accelerators, as for example, quaternary ammonium compounds; (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, as for example, kaolin and bentonite; and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well-known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, Cremophor EL (a derivative of castor oil and ethylene oxide; purchased from Sigma Chemical Co., St. Louis, Mo.), polyethyleneglycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.
Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable nonirritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 2,000 mg per day. For a normal human adult having a body weight of about 70 kg, a dosage in the range of about 0.01 to about 100 mg/kg of body weight per day is preferable. The specific dosage used, however, can vary. For example, the dosage can depend on a numbers of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to those skilled in the art.
The compounds of the present invention can exist in different stereoisomeric forms by virtue of the presence of asymmetric centers in the compounds. It is contemplated that all stereoisomeric forms of the compounds as well as mixtures thereof, including racemic mixtures, form part of this invention.
In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
The examples presented below are intended to illustrate particular embodiments of the invention, and are not intended to limit the scope of the specification or the claims in any way.
Schemes 1 through 8 below show generally how compounds of the present invention can be synthesized.
Scheme 1 illustrates a general method by which some of these compounds can be prepared, by illustrating the synthesis of [R,-(R*,S*)]-[1-{[1-(2-benzyloxy-ethylcarbamoyl)-2-(4-benzyloxy-phenyl)-ethyl]-methyl-carbamoyl}-2-(1H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester (Example 1). Coupling of Boc-NMe-Tyr(OBn)OH to 2-(phenylmethoxy)-ethylamine hydrochloride was carried out in ethyl acetate with dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBt), as coupling agents, and triethylamine as the base. The resulting product was treated with 30% trifluoroacetic acid (TFA) in methylene chloride. H-NMe-Tyr(OBn)-NHxe2x80x94CH2xe2x80x94CH2-OBn.TFA was then coupled in methylene chloride to Cbz-DHis(Trt)-OH, with benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP) as coupling agent, and diisopropylethylamine (DIEA) as the base, followed by treatment with 50% TFA in methylene chloride to give the title compound.
2-(Phenylmethoxy)-ethylamine hydrochloride was prepared by reacting 2-ethanolamine hydrochloride with sodium, followed by benzyl chloride, in toluene. The product was isolated as the HCl salt.
Scheme 2 illustrates a general method by which some of these compounds can be prepared, by illustrating the synthesis of [S-(R*,R*)]-[1-{[2-(4-benzyloxy-phenyl)-1-phenethylcarbamoyl-ethyl]-methyl-carbamoyl}-2-(1H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester (Example 2). Coupling of Boc-NMe-Tyr(OBn)-OH to 2-phenethylamine was carried out in methylene chloride:dimethylformamide (DMF) (1:1) with dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBt), as coupling agents. The resulting product was treated with 25% trifluoroacetic acid (TFA) in methylene chloride. H-NMe-Tyr(OBn)-NHxe2x80x94CH2xe2x80x94CH2-phenyl. TFA was then coupled in methylene chloride:DMF (1:1) to Cbz-His(Trt)-OH with (O-(7-azabenzotriazol-1-yl) 1,1,3,3-tetramethyl uronium hexafluorophosphate (HATU) and 1-hydroxy-7-azabenzotriazole (HOAt) as coupling agents, and diisopropylethylamine (DIEA) as the base, followed by treatment with 50%TFA in methylene chloride to give the title compound.
Scheme 3 illustrates a general method by which some of these compounds can be prepared, by illustrating the synthesis of [S-(R*,R*)]-[1-{[2-(4-benzyloxy-phenyl)-1-(2-methyl-2-phenyl-propylcarbarmoyl)-ethyl]-methyl-carbamoyl}-2-(1H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester (Example 3). Coupling of Boc-NMe-Tyr(OBn)-OH to xcex2,xcex2-dimethylphenethylamine hydrochloride was carried out in methylene chloride:DMF (3:1) with dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBt), as coupling agents, and DIEA as the base. The resulting product was treated with 25% trifluoroacetic acid (TFA) in methylene chloride. H-NMe-Tyr(OBn)-NHxe2x80x94CH2xe2x80x94C(CH3)2-phenyl. TFA was then coupled in methylene chloride to Cbz-His(Trt)-OH, with benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP) as coupling agent, and diisopropylethylamine (DIEA) as the base, followed by treatment with 50%TFA in methylene chloride to give the title compound.
xcex2,xcex2-Dimethylphenethylamine hydrochloride was obtained from benzyl cyanide, which was treated with 2 equivalents of sodium hydride in tetrahydrofuran (THF) and 2 equivalents of methyl iodide in THF, followed by hydrogenation (H2, Pd/C, ammonia/CH3OH). The product was isolated as the hydrochloride salt.
Scheme 4 illustrates a general method by which some of these compounds can be prepared, by illustrating the synthesis of [S-(R*,R*)]-[2-(1H-imidazol-4-yl)-1-(methyl-{1-(2-methyl-2-phenyl-propylcarbamoyl)-2-[4-(pyridin-2-ylmethoxy)-phenyl]-ethyl}-carbamoyl)-ethyl]-carbamic acid benzyl ester (Example 4). Coupling of Boc-NMe-Tyr-OH to xcex2,xcex2-dimethylphenethylamine hydrochloride was carried out in THF with dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBt), as coupling agents, and triethylamine as the base. Boc-NMe-Tyr-NHxe2x80x94CH2-C(CH3)2-phenyl was dissolved in THF and treated with 2-pyridylcarbinol and triphenylphosphine followed by diethyl azodicarboxylate, under a nitrogen atmosphere. The resulting product was treated with 33% trifluoroacetic acid (TFA) in methylene chloride. H-NMe-Tyr(Oxe2x80x94CH2-(2-pyridyl))-NHxe2x80x94CH2xe2x80x94C(CH3)2-phenyl. TFA was then coupled in methylene chloride to Cbz-His(Trt)-OH, with benzotriazole-1-yl-oxy-tris-pyrrolidino phosphonium hexafluorophosphate (PyBOP) as coupling agent, and diisopropylethylamine (DIEA) as the base, followed by treatment with 80% aqueous acetic acid (HOAc) at 87xc2x0 C. to give the title compound.
Scheme 5 illustrates a general method by which some of these compounds can be prepared, by illustrating the synthesis of [S-(R*,R*)]-2-(3-benzyl-3-methyl-ureido)-N-[2-(4-benzyloxy-phenyl)-1-(2-methyl-2-phenyl-propylcarbarmoyl)-ethyl]-3-(1H-imidazol-4-yl)-N-methyl-propionamide (Example 5). Coupling of Boc-NMe-Tyr(OBn)-OH to xcex2,xcex2-dimethylphenethylamine hydrochloride was carried out in chloroform with benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP) as coupling agent, and triethylamine as the base. The resulting product was then treated with a saturated solution of HCl in diethyl ether to give H-NMe-Tyr(OBn)-NHxe2x80x94CH2xe2x80x94C(CH3)2-phenyl.HCl (B).
H-His(Trt)-OCH3 hydrochloride was reacted with 4-nitro-phenyl-chloroformate in the presence of triethylamine in methylene chloride, followed by the addition of benzylmethylamine. Saponification was then carried out with 1N NaOH in methanol:THF (1:1) followed by treatment with 1N HCl to give phenyl-CH2xe2x80x94N(CH3)xe2x80x94CO-His(Trt)-OH (A).
Products A and B were then coupled in chloroform with benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP) as coupling agent, and DIEA as the base. The resulting product was then treated with 80% aqueous acetic acid at 90xc2x0 C. to give the title compound.
Scheme 6 illustrates a general method by which some of these compounds can be prepared, by illustrating the synthesis of [S-(R*,R*)]-[1-({2-(4-benzyloxy-phenyl)-1-[(1-phenyl-cyclobutylmethyl)-carbamoyl]-ethyl}-methyl-carbamoyl)-2-(3H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester (Example 6). Coupling of Boc-NMe-Tyr(OBn)-OH to C-(1-phenyl-cyclobutyl)-methylamine hydrochloride was carried out in methylene chloride with 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) as coupling agent, and DIEA as the base. The resulting product was treated with 20% trifluoroacetic acid (TFA) in methylene chloride. (S)-3-(4-Benzyloxy-phenyl)-2-methylamino-N-(1-phenyl-cyclobutylmethyl)-propionamide trifluoroacetate salt was then coupled in methylene chloride to Cbz-His(Trt)-OH with HBTU as coupling agent, and diisopropylethylamine (DIEA) as the base, followed by treatment with 50%TFA in methylene chloride to give the title compound.
Scheme 7 illustrates a general method by which some of these compounds can be prepared, by illustrating the synthesis of [S-(R*,R*)]-(2-(3H-imidazol-4-yl)-1-{methyl-[1-(2-methyl-2-phenyl-propylcarbamoyl)-2-phenyl-ethyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester (Example 7). Coupling of Boc-NMe-Phe-OH to xcex2,xcex2-dimethylphenethylamine hydrochloride was carried out in methylene chloride with dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBt), as coupling agents, and DIEA as the base. The resulting product was treated with 30% trifluoroacetic acid (TFA) in methylene chloride. H-NMe-Phe-NHxe2x80x94CH2xe2x80x94C(CH3)2-phenyl.TFA was then coupled in methylene chloride to Cbz-His(Trt)-OH with HATU and HOAt as coupling agents and diisopropylethylamine (DIEA) as the base, followed by treatment with 50%TFA in methylene chloride to give the title compound.
Scheme 8 illustrates a general method by which some of these compounds can be prepared, by illustrating the synthesis of [S-(R*,R*)]-(2-(3H-imidazol-4-yl)-1-{methyl-[3-methyl-1-(2-methyl-2-phenyl-propylcarbamoyl)-butyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester (Example 8). Coupling of Boc-NMe-Leu-OH to xcex2,xcex2-dimethylphenethylamine hydrochloride was carried out in methylene chloride:DMF (1:1) with HBTU as coupling agent, and DIEA as the base. The resulting product was treated with 25% trifluoroacetic acid (TFA) in methylene chloride. H-NMe-Leu-NHxe2x80x94CH2xe2x80x94C(CH3)2-phenyl.TFA was then coupled in methylene chloride:DMF (4:1) to Cbz-His(Trt)-OH, with HBTU as coupling agent, and diisopropylethylamine (DEA) as the base, followed by treatment with 50%TFA in methylene chloride to give the title compound. 
The following abbreviations are used herein: